Preparation of N-tBoc l-glutathione dimethyl and di-tert-butyl esters: Versatile synthetic building blocks

The title l-glutathione derivatives, containing acid- and base-labile esters, respectively, were obtained in good overall yields. N-tBoc l-glutathione dimethyl ester was prepared via Fischer esterification of l-glutathione disulfide (GSSG) using HCl in dry methanol, protection of the amine with tBoc2O, and tributylphosphine cleavage of the disulfide in wet isopropanol. Alternatively, Fischer esterification and tBoc-protection of l-glutathione (GSH) also furnished N-tBoc glutathione dimethyl ester accompanied by a small amount of S-tBoc that was removed chromatographically. The di-tert-butyl ester was obtained by S-palmitoylation of GSH in TFA as solvent, N-tBoc-protection, esterification using tBuOH mediated by diisopropylcarbodiimide/copper(I) chloride, and saponification of the thioester. These l-glutathione derivatives are versatile synthetic building blocks for the preparation of S-glutathione adducts.

The title l-glutathione derivatives, containing acid- and base-labile esters, respectively, were obtained in good overall yields. N-tBoc l-glutathione dimethyl ester was prepared via Fischer esterification of l-glutathione disulfide (GSSG) using HCl in dry methanol, protection of the amine with tBoc2O, and tributylphosphine cleavage of the disulfide in wet isopropanol. Alternatively, Fischer esterification and tBoc-protection of l-glutathione (GSH) also furnished N-tBoc glutathione dimethyl ester accompanied by a small amount of S-tBoc that was removed chromatographically. The di-tert-butyl ester was obtained by S-palmitoylation of GSH in TFA as solvent, N-tBoc-protection, esterification using tBuOH mediated by diisopropylcarbodiimide/copper(I) chloride, and saponification of the thioester. These l-glutathione derivatives are versatile synthetic building blocks for the preparation of S-glutathione adducts.Figure optionsDownload as PowerPoint slide